What if we could use positive memories as a weapon to suppress certain symptoms associated with mood disorders like depression, for example bringing back a memory that was once thought to be lost in a patient with Alzheimer's. Or going in and turning the dial down on the emotional gut-wrenching I hate my life feeling of something like PTSD. Imagine being able to turn the dial down on those negative emotions.

Alright, so to start off, just by a show of hands who here would erase a memory of an ex-boyfriend or girlfriend? This is like therapy session for me to make myself feel better, so...

So, the work that I've been doing at MIT... focuses, more seriously, on finding individual memories in the brain and trying to actually tinker with those memories. Can we turn them on, can we turn them off can we change the contents of those memories? Ethical stuff aside, you can imagine the implications for things like actually being able to activate memories in Alzheimer's, for example. Or using memories to combat certain symptoms associated with psychiatric disorders.

So, let's take a step back to... if we're going to go into the brain and look for a memory where would we actually look? How do we find a memory in the sea of the... eighty-six billion brain cells that you have?

So, this is a picture of me drowning in the Dominican Republic. This was a few years back on spring break and I went with a couple of friends and... Dominican Republic, spring break, awesome. Kayaking in the ocean, terrible idea. Because it feels like you're on an aquatic treadmill the entire time not getting anywhere. Inevitably, you capsize and also inevitably, your very good friends sit on shore taking pictures of you dying. So, when I'm recalling this memory of nearly drowning in the Dominican Republic what brain areas are lighting up, right? Like, where would you actually go and see this particular memory? If you were to ignore all human ethics for a second and slice up my brain, you would see that one of the areas that really lights up is an area called the hippocampus. You've probably heard of this as It's one of the more popular brain areas. It's what Dory from Finding Nemo probably had damaged it's what... It's what Matt Damon in the Bourne Trilogy probably had damaged, or just Matt Damon in general. And... So, the hippocampus really lights up. So, this gives us a hint as to where we can go into the brain and actually look for a particular memory.

The main question that we started off tackling in grad school is can we go in, can we find the brain cells that are active during a particular memory and again, can we actually modulate those brain cells. So, what we would do is, uh, we would go in we would find these brain cells that we think are holding on to a particular memory and we would actually artificially install a light-sensitive switch in those brain cells. So, that means that we can actually take an optic fiber, do some careful brain surgery and actually shoot lasers into the brain and reactivate these brain cells or inactivate these brain cells that we think are housing a particular memory. This is my favorite picture that I have taken in all of graduate school. If you were to slice your hippocampus along this direction going back and back and back, this is what it would look like. And what we have here is brain cells that are holding on to a particular fear memory, in this case. And not only have these cells been tricked to... respond to pulses of light but they've also been tricked to just glow green. So, what you're looking at is actually what a cross-section of a memory looks like at the level of the brain. Where the seemingly ephemeral stuff that you can't really go in and poke you can actually go in and, if you have a small enough finger actually poke and isolate those brain cells. That's what a memory looks like at the level of the brain. So, given this technique now of actually going in and shooting light into the brain we wanted to ask, can we just activate a memory. Can we go in, can we flick it on?

This is just an example of one of the mice that we use and we can actually go in and again, shoot lasers into the brain. The brain doesn't have any pain receptors, so... no mice were harmed, I guess, in this process. The experiment is actually reasonably straightforward. All we do is we put an animal in a blue box. Or we'll just call it box A. And then we give it a couple of mild foot shocks, just... it has to form a memory, right? So, it forms a fear memory of those mild foot shocks. So, it's like static, right? It doesn't really hurt. So, it's more of the surprise. So, they form this fear memory and we find the brain cells that are active when the animal is actually forming this particular memory and we trick those brain cells to respond to just the brief pulses of light. So, the million-dollar experiment now is we put the animal in a completely different environment where nothing bad has happened to them. And then we shoot light into the brain and we ask is it thinking about the fear memory of the blue box. Now, in animals, uh, we used fear just because it's super easy to measure. You can tell when an animal is scared. So, fear manifests itself in mice as the animal just going huddling in a corner in an immobilized posture not wanting to move 'cause it doesn't want to be detected by a predator. We call that freezing because the animal looks like it's frozen in place. This was the very first animal that we ran, 2011. So, this animal it's in environment B, it has no reason to be scared about the environment. It's running around, it's sniffing around it's minding its own business. We turn the light on and as you can see its behavior doesn't really dramatically change. That's a good thing. Then the same exact animal, we give it a fear memory. We trick that fear memory to respond to a pulse of light. And now it's in this environment again has no reason to be scared about it. It's running around, minding its own business. And then you shoot light into the brain and it goes into that freezing posture. So, that was our first successful demonstration that we can actually bring back to life a particular fear memory in the brain.

Well, if we can actually tinker with a particular memory could we try to create a false memory? Can we change the contents of a memory? To try to create a false memory what we would do is we would put our animals in, once again, a blue box. And then, very simple, we just find the brain cells that are active when the animal is forming this particular memory of the blue box. We would trick those brain cells to respond to pulses of light. Next, we put the animals in a red box. Very different environment different sights, sounds, smells, the works. And then we give it a couple of mild foot shocks so that it's forming a fear memory. But while we give them these mild foot shocks we shoot light into the brain so that it recalls the memory of the blue box So, that's the attempt to try to associate the memory of the blue box where nothing happened and the aversive information coming into the animal in the form of a foot shock. So, the test here is when we put it now in the blue box it should be scared, even though nothing bad technically happened in that blue box. And that's exactly what happens. These animals, when we put them back in the blue box show that fearful behavior, even though they have no reason to technically be scared about it. So, to what end... like, why are we going in and actually manipulating memories why are we going in and activating fear memories and so on.

Now, let's take a step back to the 1950s. The 1950s saw a very real massive revolution in neuroscience and pharmacology. Every single drug that's available today Prozac, anxiolytics, the works are iterations of their 1950's counterparts. Every single one, it's amazing. And yet, in a decade that revolution stalled. Every single drug today is basically the same as the one in the 1950s. That's not okay, that's not how you improve a field. So, what happened, I would argue, is that we stopped thinking outside the box. We started studying drugs, and we stopped studying people. We saw them as moneymakers and not actually going in and trying to treat these diseases that have been around with us for as long as we've had the ability to feel. So, for my last project in graduate school, I thought somewhat not modestly, can we just restart this revolution. Can we actually think outside the box and just use novel approaches to try to intervene with some of these psychiatric disorders. So... we thought, given this memory manipulation technology could we actually go in and activate let's say, something like a positive memory. What if we could use positive memories as a weapon to suppress certain symptoms associated with mood disorders like depression, for example. So, in humans it's really intuitive, right? Positive memories feel good. Memory of the Red Sox winning the World Series for me feels fantastic. And, if you're from New York, I'm sorry I'm not sorry. So... And... memories of Cape Cod also feel amazing for me. These things they are actually naturally rewarding. They light up a lot of the circuitry that lights up when you have Pepsi or when you actually undergo some other rewarding experiences. 

This begs the question, well, we're working with mice, so what does a positive memory actually look like in a mouse? Um, it's pretty straightforward. When you expose a male mouse to a female mouse they go bananas over it, so we put male mice in box with female mice and if you've been to a bar at like one-thirty in the morning you know exactly what this behavior looks like. Also conserved across the evolutionary ladder. So what we can do is we can find the brain cells that are active when the animal is forming this particular positive experience. Once again, trick those brain cells to respond to pulses of light. So, we wanted to ask can we actually go and intervene in some of these disorders and to what extent can we actually model these in animals. So... one task that we use to measure in this case, the inability to experience or seek out pleasure also known as anhedonia, right. We give these animals a choice between sugar water and regular water. Now, animals that don't show symptoms associated with depression, for example choose sugar water about 80 percent of the time. It tastes better, it's like Coca-Cola or Pepsi like, it's just something that they find more rewarding. Animals that show symptoms associated with depression, on the other hand show a 50-50 preference for sugar water and regular water. That's what we consider the inability to actually go out and find or experience pleasure in the world. But what if we can activate a positive memory? What happens to that symptom of anhedonia of not being able to experience pleasure? What happens is the animals immediately prefer sugar water about 80 percent of the time. So, we were successfully able to suppress that symptom associated with depression simply by harnessing the brain's internal powers and just jump-starting a positive memory. What if you actually go and reactivate these positive memories over and over and over again, right? We all know our personalities exist along a spectrum. Some people are slightly more optimistic some people are a little bit more ee-ee-ee... And, this just it exists there's a spectrum of differences in, this kind of, mood. So... all we did was we went into the brain we reactivated this positive memory over and over and over again, for about a week. And actually, not only did it actually suppress a medley of symptoms associated with depression it actually increased the number of new born brain cells. The brain actually grew as a result. It's almost as if we were harnessing the brain's natural powers and we forced it to fix itself. And it fixed itself by making new brain cells. 

This begs the inevitable question should we actually... should we do this in humans? I mean, the technology doesn't exist yet but it's important that we start this conversation yesterday so that we can actually have the proper social and legal infrastructure for these kind of things that actually might be possible. Again, you don't have to imagine any more the possibility of bringing back a memory that was once thought to be lost, in a patient with Alzheimer's. Or imagine going in and turning the dial down on the emotional gut-wrenching I hate my life feeling of... not a breakup but something more seriously, something like PTSD. Imagine being able to turn the dial down on those negative emotions. Or being able to jump start particular moods when your mood is really low or even under depression, uh, in a depressed state. So, those are the things that we don't have to imagine any more. Those are the things that we are on the cusp of actually being able to do with, I think, powerful therapeutic value. Now... we know so much from this animal research because in this case, you know, there's a lot of brain areas that are actually conserved across the evolutionary ladder. And, uh... both processes, memory and psychiatric disorders they are just this physical as, say a broken leg. Like, we know that in humans a broken leg will give you broken locomotion. And we know that, through neuroscience we know that broken brains give rise to broken thoughts. Both still require physical intervention. And in order to come up with new interventions we have to continue to actually explore... exploration, that's the right word. Because that means actually reaching that edge of what is known and unknown and truly pushing forward. And thereby, we make the unknown known. Thank you.